Fibrin sealants, also known as fibrin glue, have been in use in the clinic for decades (see, for example, Tabélé, et al. J Pharm Pharmaceut Sci 2012, 15:124-140; Dickneite, G et al. Thrombosis Res 2003, 112:73-82). Oftentimes, fibrin sealants consist of two liquid components, a fibrinogen comprising component and a thrombin comprising component, which are stored frozen due to their inherent instability. Sometimes fibrin sealant products consist of two freeze dried components, which require reconstitution immediately prior to use and delivery by a conjoined syringe or other double-barreled delivery device. Freeze dried formulations are typically stable, but the fibrinogen component is difficult to reconstitute. Upon mixing the two-component solutions, thrombin cleaves fibrinogen thus allowing the latter to generate fibrin polymers.
A fibrin sealant clot is formed by enzymatic reactions involving fibrinogen, thrombin and Factor XIII. Fibrinogen is the precursor protein of the blood clot matrix. It has a molecular weight of ˜340,000 Daltons and consists of 3 pairs of non-identical polypeptide chains, Aα, Bβ and γ, linked together by disulfide bonds. Fibrinogen has a trinodular structure: two identical D terminal globular domains and a central E globular domain connected by supercoiled α-helices. Thrombin converts the fibrinogen to fibrin monomers by enzymatic action at a rate determined by the concentration of thrombin.
Factor XIII, an enzyme of the blood coagulation system, typically present in the glue formulation, cross-links and stabilizes the fibrin clot when activated by thrombin and in the presence of calcium. This process bypasses most of the steps of normal coagulation and mimics its last phase. Some manufacturers add anti-proteolytic agents to the fibrin glue formulation (e.g. as described in WO93/05822) or specifically remove the plasminogen in order to stop or delay fibrinolysis (e.g. as described in U.S. Pat. Nos. 5,792,835 and 7,125,569).
Background art includes Laudano and Doolittle (PNAS 75(7):3085-9) and U.S. Pat. Nos. 5,219,328; 5,318,524; 8,367,802; 5,750,657; 6,262,236; 6,268,483; 6,500,427; 5,723,579; 5,478,810; 5,607,858; 6,908,899 and 8,513,380.